Alpha-phenyl-4-pyridinemethyl 2, 2-dimethyl-3-(2-methylpropenyl) cyclopropylcarboxylate



United States Patent ()fi ice 3,098,857. Patented July 23, 19633,098,857 u-PHENYL 4 PYRIDINEMETHYL 2,2-DIMETHYL- 3 (2NETHYLPROPENYL)CYCLOPROPYLCAR- BOXYLATE Kurt J. Rorig, Glenview, Ill.,assignor to G. D. Searle & Co., Chicago, EL, a corporation of DelawareNo Drawing. Filed Nov. 3, 1961, Ser. No. 149,859 1 Claim. (Cl. 260-295)This invention relates to aryl (cyclic amino)alkyl esters ofheterocyclic and alicyclic carboxylic acids and to a pror ss for theirmanufacture. More particularly, this invention relates to compounds ofthe formula Het wherein Het designates a nitrogenous heterocyclicradical optionally alkylated or aralkylated; Ar designates hydrogen oran aromatic carbocyclic radical optionally alkylated, ialkoxylated, orhalogenated; R designates hydrogen or an alkyl or phenyl radical; Alkand Alk each designate a lower alkylene or alkenylene radical; n and ineach designate O or the positive integer 1; and R" designates a furyl,thienyl, pyridyl, or optionally substituted cycloalkyl radical.

The application for Letter-s Patent securing the invention hereindescribed and claimed is a continuation-inpart of applicants priorcopending application Serial No. 805,722, filed April 13, 1959.

Among the cyclic amino radicals represented by Het in the foregoingformula are pyridyl, piperidyl, pyrrolidyl, quinolyl, andtetrahydroquinolyl groupings. Of these groupings, those wherein theimino function is present can, in any given instance, be substituted onthe nitrogen atom by especially a lower alkyl or an aralkyl radical. Thelower alkyl radicals contemplated include methyl, ethy, propyl,isopropyl, butyl, isobutyl, sec-butyl tertbutyl, pentyl, isopentyl,tert-pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, and like C Hradicals wherein s is an integer amounting to less than 9. Illustrativeof the aralkyl radicals occasionally present are such as benzyl andphenethyl groupings.

As to the aromatic carbocyclic radicals designated by Ar in thestructural formula these are principally phenyl or naphthyl groupingswhich can comprise, in place of nuclear hydrogen, 1 or more straightorbranched-chain alkyl or alkoxy radicals, or halogen, or combinations ofthese substituents, the alkyl and alkoxy substituents ordinarily beingof lower order, which is to say embracive of fewer than 9 carbon atoms.

The lower alkylene and alkenylene radicals represented by Alk and Alk inthe formula are bivalent acyclic straightor branched-chain hydrocarbonmoieties, saturated or containing not more than 1 double bond, andtypified by methylene, ethylene, vinylene, trimethylene, propylene,1,3-propenylene, tetramethylene, 2-methyl-1,3- propenylene, and2,2-dimethyl-1,3-propylene groupings. It will be recognized that when nor m in the formula is 0, the apposed term drops out; and when both 11and m are 0, the compounds referred to can be depicted Het O be such ascyclopropyl, cyclopentyl, cyclohexyl, and the like substituted adlibitum by particularly an isoalkenyl radical, for example, isopropenyl,isobutenyl, etc.

Equivalent to the basic amino esters of this invention for the purposesdescribed are non-toxic acid addition and quaternary ammonium saltsthereof, the compositions of which may be symbolized by wherein Het, Ar,R, R, Alk, Alk, n, and m have the meanings herein'before assigned; Q isselected from among hydrogen and lower alkyl, hydroxy(lower alkyl), andlower alkenyl radicals, as also such aralkyl radicals as benzyl,phenethyl, and naphthylmethyl; T is 1 equivalent of an -anionforexample, chloride, bromide, iodide, nitrate, phosphate, sulfate,sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate,toluenesulfonate, acetate, lactate, succinate, m-alate, maleate,tartrate, citrate, gluconate, ascorbate, benzoate, cinnamate, or thelike-which, in combination with the cationic portion of a saltaforesaid, is neither pharmacologically nor otherwise undesirable inpharmaceutical dosage, and y is 1 except when R" contains a basicnitrogen, in which case y is either 1 or 2.

The compounds herein disclosed are useful because of their valuablepharmacological properties. Thus, for example, they are characterized byeurhythmic and ataraxic effects.

The compounds to which this invention relates are preparable by avariety of methods, but the preferred procedure comprises contacting acarbinol of the formula lilet Ar-O-Alkn-OH with an acid chloride of theformula R"Alk' COCl Conversion of the amine bases of this invention toequivalent acid addition salts is accomplished by simple admixture ofthese compounds with any of various inorganic or strong organic acids,the anionic portion of which conforms to T as hereinabove defined.

The quaternary ammonium compounds comprehended by this invention arethose derived by contacting a claimed base with an organic ester of theformula Q and T being limited by the meanings hereinbefore assigned, andit being additionally provided that Q is not hydrogen. Quaternizationtakes place in the temperature range between 45 and 100, using an inertsolvent such as chloroform, acetone, butanone, methanol, butanol, or thelike as the reaction medium. Quaternization is ordinarily completed infrom 1 to 48 hours and is generally carried out in a closed system if alower alkyl halide-such as methyl chloride-is one of the reagents. Usingmethyl bromide, the manufacture of quaternary salt may be smoothlyeifected in butanone solution at the reaction time being approximately 1hour.

The following examples describe in detail certain of the compoundsillustrative of the present invention and methods which have beendevised for their manufacture. However, the invention is not to beconstrued as limited thereby, either in spirit or in scope, since itwill be apparent to those skilled in the art of organic synthesis thatmany modifications both of materials and of methods, may be practicedwithout departing from the purpose and intent of this disclosure. In theexamples hereinafter detailed, temperatures are given in degreescentigrade, pressures in millimeters of mercury, and relative amounts ofmaterials in parts by weight, except as otherwise noted.

Example 1 a-Phenyl-4-pyrz'dinemethyl 2-fur0ate.A mixture of 45 parts ofa-phenyl-4-pyridinemethanol and 100 parts of 2-furoyl chloride is heatedwith vigorous agitation at 120- 130 for 3 hours. The dark brown productis partitioned between 1000 parts of 5% aqueous caustic and 1500 partsof ether. The ether phase is extracted with 1000 parts of 5% aqueoushydrochloric acid. The acid extract is made basic by adding a slightexcess of lye, and the organic ester which separates is taken up in 1500parts of ether. The resultant solution is dried over anhydrous potassiumcarbonate and then vacuum distilled. The fraction coming over at 155-160under 0.15 mm. pressure is the desired a-phenyl-4-pyridinemethyl2-furoate, which solidifies on standing and melts at 7072.5. The producthas the formula Example 2 u-Phenyl-4-pyridinemethyl 3-furoate. Usingessentially the technique set forth in the preceding Example 1, butsubstituting 100 parts of 3-furoyl chloride for the 2-furoyl chloridecalled for therein, one obtains a-phenyl- 4-pyridinemethyl 3-furoate, ofthe formula rail ll Example 3 Example 4 oz Phenyl-4-pyridinemethyl3-thiophenecarboxylate. Using essentially the technique set forth in thepreceding Example 3, but substituting 45 parts of 3-thiophenecarbonylchloride for the 2-thiophenecarbonyl chloride called for therein, oneobtains a-phenyl-4-pyrid-inemethyl 3-thiophenecarboxylate. The producthas the formula I S CHO C U Example 5 0c Phenyl-4-pyridinemethyl 2,2-dimethyl-3-(2-methylpropenyl) cyclopropylcarboxylate.-A mixture of 93 partsof a-phenyl-4pyridinemethanol and 103 parts of2,2-dimethyl-3-(Z-rnethylpropenyl)cyclopropanecarboxylic acid chloride(chrysanthemum monocarboxylic acid chloride) in 690 parts of pyridine isheated at the boiling point under reflux with agitation for 45 minutes,whereupon the pyridine is removed by vacuum distillation and the residueis thoroughly mixed with an excess of aqueous 10% caustic. This mixtureis extracted with ether; and the ether extract is dried over anhydrouspotassium carbonate and then stripped of solvent by distillation. Theresidual light brown oil is the desired ot-phenyl-4-pyridinemethyl 2,2dimethyl 3 (2 methylpropenyl)cyclopropylcarboxylate. The product ischaracterized by a menthol-like aroma. It has the formula a Phenyl 4pyridinemethyl nicotinate dihydrobromide.Using essentially the techniqueset forth in the prceding Example 5, 93 pants ofa-phenyIA-pyridinemethanol and parts of nicotinoyl chloridehydrochloride are reacted together in 1000 parts of pyridine for 4 hoursto give a-phenyl-4-pyridincmethyl nicotinate, which melts at 5658. Thebase is taken up in hot absolute ethanol, and the resultant solution ismade acid with hydrogen bromide dissolved in absolute ethanol. Anhydrousether is then added, throwing down a granular ivory precipitate ofa-phenyl-4-pyridinemethyl nicotinate dihydrobromide. The product,recrystallized from a mixture of ethanol and ether, melts at 162-165"(with gas evolution). It has the formula r mide.Using essentially thetechnique set forth in the preceding Example 6, but substituting 120parts of isonicotinoyl chloride hydrochloride for the nicotinoylchloride hydrochloride called for therein, one obtainsu-phenyl-4-pyridinemethyl isonicotinate dihydrobromide, of the formulaExample 8 a-Phenyl-Z-pyridinemetlzyl picolinate dihydrobromide.Usingessentially the technique of Example 6, but substituting for thea-phenyl-4-pyridinemethanol and nicotinoyl chloride hydrochloride calledfor therein 93 pants of ot-phenyl-2-pyridinemethanol and 120 parts ofpicolinoyl chloride hydrochloride, respectively, one ob- 6 tainsa-phenyI-Z-pyridinemethy1 picolinate dihydrobro- What is claimed is:mide. The product has the formula a-Phenyl-4-pyridinemethyl2,2-dimethy1-3-(2 methylpropenyl) cyclopropylcarb oxylate.

5 References Cited in the file of this patent 0 UNITED STATES PATENTS NI IL 2NBI 3,029,246 R-orig Apr. 10, 1962 l OTHER REFERENCES 10 Villaniet 211.: J. Org. Chem, vol. 17, pp. 249-54

